A Novel Heme-Regulatory Motif Mediates Heme-Dependent Degradation of the Circadian Factor Period 2

Yang, Jianhua; Kim, Kevin D.; Lucas, Andrew T.; Drahos, Karen E.; Santos, Carlo; Mury, Sean P.; Capelluto, Daniel G. S.; Finkielstein, Carla V.

doi:10.1128/mcb.00236-08

Cited by 92 publications

(95 citation statements)

References 47 publications

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“…Although mPER proteins do not have known sensory functions, mPER2 has been reported to bind heme as a cofactor in its PAS domains and in its C-terminal region (13,14). Our UV/ VIS spectroscopic analyses (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To find out, if mPER1 and mPER3, like mPER2 (14,15), are able to bind heme in their PAS domains, we have incubated our purified mPER3[108-411], mPER3 , and mPER1 proteins with heme, separated the heme exposed proteins via gel filtration chromatography and assessed heme binding by UV/VIS spectroscopy. For all three fragments we observed a shift of the absorption maximum from 390 nm (free heme) to about 420 nm (protein-bound heme, Fig.…”

Section: Analysis Of Mper Pas Domain Interactions In Solutionmentioning

confidence: 99%

“…These interactions regulate the stability and cellular localization of the mPERs and modulate the activity of the mBMAL1/mCLOCK transcription factor complex. Additionally, the PAS domains of NPAS2, mCLOCK, and mPER2 have been reported to bind heme (13)(14)(15)(16). In the circadian clock, mPER1 and mPER2 proteins are found in large protein complexes, likely establishing multiple interactions via their PAS domains, the central CKIε∕δ binding domain and the C-terminal mCRY binding region (17)(18)(19).…”

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confidence: 99%

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Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

Kucera

Schmalen

Hennig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The three PERIOD homologues mPER1, mPER2, and mPER3 constitute central components of the mammalian circadian clock. They contain two PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B), which mediate homo-and heterodimeric mPER-mPER interactions as well as interactions with transcription factors and kinases. Here we present crystal structures of PAS domain fragments of mPER1 and mPER3 and compare them with the previously reported mPER2 structure. The structures reveal homodimers, which are mediated by interactions of the PAS-B β-sheet surface including a highly conserved tryptophan (Trp448 mPER1 , Trp419 mPER2 , Trp359 mPER3 ). mPER1 homodimers are additionally stabilized by interactions between the PAS-A domains and mPER3 homodimers by an N-terminal region including a predicted helix-loop-helix motive. We have verified the existence of these homodimer interfaces in solution and inside cells using analytical gel filtration and luciferase complementation assays and quantified their contributions to homodimer stability by analytical ultracentrifugation. We also show by fluorescence recovery after photobleaching analyses that destabilization of the PAS-B/tryptophan dimer interface leads to a faster mobility of mPER2 containing complexes in human U2OS cells. Our study reveals structural and quantitative differences between the homodimeric interactions of the three mouse PERIOD homologues, which are likely to contribute to their distinct clock functions.circadian clock | PAS domains | PERIOD proteins | protein interactions

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Mper Pas Domain Interactions In Solutionmentioning

confidence: 99%

mentioning

confidence: 99%

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Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

Kucera

Schmalen

Hennig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In this process, Bmal1-CLOCK heterodimers activate the transcription of clock-controlled genes, including Rev-erb␣/␤, Per, and Cry. The binding of heme to the HRM of Period 2 (Per2) enhances its proteasomal degradation in immortalized cells (97). Heme also has been shown to dampen Per2 rhythm in mouse suprachiasmatic nucleus explants (98).…”

Section: An Unknown Factor Present In Cell Extracts Mediates the Effementioning

confidence: 99%

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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Rev-erb␣ and Rev-erb␤ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erb␣ recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erb␤ (FLRev-erb␤) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo-and heme-replete FLRev-erb␤⅐DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erb␤⅐NCoR1 complex. The interaction between FLRev-erb␤ and NCoR1 as well as Reverb␤ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erb␤ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10 ؊6 s ؊1 ) of heme dissociation from Rev-erb␤ rules out a prior proposal that Reverb␤ acts as an intracellular heme sensor.Nuclear receptors (NRs) 2 are eukaryotic transcription factors that activate or repress gene expression in response to binding small signaling molecules such as steroid hormones, lipophilic vitamins, and fatty acids (1). Genes regulated by NRs are involved in a myriad of cellular processes ranging from metabolic homeostasis to growth and development. The subjects of this article, Rev-erb␣ and Rev-erb␤, are NRs that have overlapping functions and tissue expression patterns (2-9) and are under circadian control (10 -12). Rev-erb NRs repress the transcription of key genes, e.g. Bmal1, CLOCK, and Rev-erb␣ itself, involved in regulating the molecular clock (13)(14)(15). This is accomplished in part through the formation of a heterodimeric Bmal1-CLOCK complex that activates the transcription of clock-controlled genes including Rev-erb␣/␤, completing a critical feedback loop required for circadian rhythm maintenance (6, 7). Rev-erb␣ and Rev-erb␤ also regulate the expression of genes involved in gluconeogenesis, lipid homeostasis, and immune responses, ultimately synchronizing these processes to the diurnal cycle (16 -21).The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22, 23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to ...

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“…In combination with the nearby CRY1 disulphide bond formation, the zinc ion regulates the formation of the PER2/CRY1 complex, probably influenced by the redox state of the cell [82]. A haem-regulatory motif was previously described in the C-terminus of PER2, affecting its stability through interaction with its partner CRY1 [84]. In addition, the AMP-activated protein kinase (AMPK) pathway regulates the stability of CRY proteins.…”

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confidence: 99%

Interplay between cellular redox oscillations and circadian clocks

Rey

Reddy

2015

Diabetes Obesity Metabolism

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The circadian clock is a cellular timekeeping mechanism that helps organisms from bacteria to humans to organize their behaviour and physiology around the solar cycle. Current models for circadian timekeeping incorporate transcriptional/translational feedback loop mechanisms in the predominant model systems. However, recent evidence suggests that non-transcriptional oscillations such as metabolic and redox cycles may play a fundamental role in circadian timekeeping. Peroxiredoxins, an antioxidant protein family, undergo rhythmic oxidation on the circadian time scale in a variety of species, including bacteria, insects and mammals, but also in red blood cells, a naturally occurring, non-transcriptional system. The profound interconnectivity between circadian and redox pathways strongly suggests that a conserved timekeeping mechanism based on redox cycles could be integral to generating circadian rhythms. Keywords: biological rhythms, circadian clock, metabolic oscillator, redox biology Date submitted 9 April 2015; date of final acceptance 7 May 2015 IntroductionCircadian rhythms are ubiquitous biological rhythms with a period of about 24 h that are generated by single-cell molecular clocks. These cellular timing systems orchestrate a multitude of metabolic processes as uncovered by several global surveys of rhythmic transcripts [1], proteins [2] and metabolites [3,4]. Early studies in the field of cellular metabolism highlighted the existence of short-period cycles, for example, photosynthesis, glycolysis, Krebs cycle and purine nucleotide cycle, in order to maintain intracellular homeostasis. However, recent evidence of redox cycles on the circadian time scale has suggested a much tighter integration between circadian and metabolic cycles. Indeed, rhythms in the oxidation of a family of antioxidant proteins, the peroxiredoxins (PRDXs), have been described from bacteria to humans [5][6][7][8]. Such redox oscillations exist even in the absence of transcription, indicating a pure biochemical 24-h cycle. This suggests an unanticipated contribution of metabolism to circadian timekeeping, and forces the consideration of new models that incorporate energy metabolism as an integral part of circadian oscillators, rather than simply an output of the latter.The current models of the circadian clock in eukaryotes rely on similar transcription/translation feedback loops, even though the specific components within these genetic structures vary from species to species [9]. In mammals, the basic helix loop helix (bHLH) transcription factors BMAL1/CLOCK (or the close homologue NPAS2) are the main transcriptional activators [10]. Using E-box DNA regulatory elements, they activate their target genes Period (Per1/2/3), Cryptochrome (Cry1/2) and Rev-Erb (Rev-Erb / ). After a delay, PER and CRY proteins repress their own activation by BMAL1/CLOCK, closing the negative feedback loop. The haem-sensing transcriptional repressors REV-ERBs inhibit the transcription of the Bmal1 gene in the late afternoon and shape its circadian expression...

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A Novel Heme-Regulatory Motif Mediates Heme-Dependent Degradation of the Circadian Factor Period 2

Cited by 92 publications

References 47 publications

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Interplay between cellular redox oscillations and circadian clocks

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